The present invention relates to a novel and improved process for purifying a solution of an ampicillin pro-drug ester from contaminants originating from the manufacture thereof. The novel process is of special value in connection with the removal of basic components used to neutralize acidic ones liberated in the synthesis of the ampicillin pro-drug ester referred to.
One of the commercially important ampicillin pro-drug esters is bacampicillin, or a salt thereof, such as bacampicillin hydrochloride. The final step in the manufacture thereof can generally be represented by the following reaction scheme: 
Thus, the penicillin G ester II is reacted with phosphorous pentachloride at low temperature followed by an alcohol, e.g. methanol, and water, and the 1xe2x80x2-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid (6APA) formed thereby (formula IIIa) is then reacted with phenylglycine chloride hydrochloride (formula IV) under such conditions that bacampicillin hydrochloride of formula Ia is formed. Said conditions involve the presence of DMA (N,N-dimethylaniline) or other bases to bind the hydrochloric acid liberated in the reaction. If said base is not efficiently removed in the isolation of bacampicillin hydrochloride, it will contaminate the final product to be used in a pharmaceutical preparation. Moreover, since DMA has proven to possess potential health hazards, it is necessary to eliminate said contaminant to as great an extent as possible.
In spite of the availability of several purification techniques which may seem efficient when used alone in other connections, it has, however, not previously been possible in practice to develop a process which fulfills the requirements. Apart from being inadequate as far as the purity of the end product is concerned, such techniques have also involved some inactivation of said esters.
One method of improving the purification operation is disclosed in Swedish patent No. 7810122-7, which discloses a method of removing DMA from some ampicillin pro-drug esters by means of a step wherein a specific cation exchanger is utilized.
The present invention is based on a simple and very efficient alternative to said ion exchange resin operation, which has been shown to result in improved yields as well as higher purity of the desired end product, in spite of the fact that the novel process claimed involves a crystallization operation, against which there was a prejudice in the prior art.